Diabetes mellitus in rats alters the external and internal morphology of vascular smooth muscle and endothelial cells. Even before such abnormalities exist, the functional reactivity to vasodilators and vasoconstrictors may be altered and the vessel distensibility may be compromised. The endothelial cell abnormalities may impair the production and release of endothelial derived relaxing factors and the vascular smooth muscle cells may not be able to appropriately decrease tension when exposed to endothelial dependent and nonendothelial dependent vasodilators. The net effect of these abnormalities may be a vasculature which both functionally and mechanically has a decreased functional and mechanical ability to dilate and abnormal constrictor responses. This hypothesis will be tested in streptozotocin diabetic rats with moderate and severe hyperglycemia for various durations using a technique which will allow the same intestinal arterioles and small arteries in an animal to be observed from normal life to advanced diabetes. Acute studies in these animals will be used to determine if vascular abnormalities in the skeletal muscle and cerebral vasculatures parallel those in the intestinal vasculture. The data obtained will be used to determine when in the time course of moderate and severe hyperglycemia the functional and mechanical characteristics of resistance vessels are impaired, the cellular morphology associated with in vivo abnormalities and where the greatest hemodynamic alterations occur in a given vasculature. In subsequent studies, normoglycemia will be restored in diabetic rats from 2 days to 9 weeks and again the same intestinal vessels will be studied during diabetic life and insulin treatment. The sequence of improvements in functional and mechanical properties of the vasculture will be evaluated after restoration of normoglycemia to determine which vascular abnormalities can be rapidly corrected by restoration of normoglycemia versus those which require prolonged treatment and possibly major improvement of the cellular function and morphology of diabetic vessels.